Tham salts



3,322,767 THAM SALTS Gabriel G. Nahas, 114 Chestnut St., Englewood, NJ.07631 No Drawing. Continuation of application Ser. No. 284,845, June 3,1963. This application Apr. 25, 1966, Ser. No. 545,168

Claims. (Cl. 260-258) This application is a continuation of copendingapplication Ser. No. 284,845, filed June 3, 1963, which is nowabandoned.

This invention relates to novel therapeutic agents which are acid saltsof tris (hydroxymethyl) aminomethane, referred to hereinafter as THAMand THAM metallic complexes.

My own United States Patent No. 3,055,805 relates to the use of THAM inthe treatment of acidosis.

The THAM active ingredient in carrying out the invention of my ownaforementioned patent may be in the form of the free base, or, in theform of an acid salt (citrate, acetate, lactate) thereof, which releasesthe free base and the ionized amine in the body. Furthermore, when THAMis administered as a free salt it rapidly combines with the acids(carbonic acid, lactic acid, citric acid) present in the circulatingblood to form salts (bicarbonate, lactate or citrate). Examples of acidsalts conventionally used as pharmacologically acceptable acid salts oftherapeutically active amine buffers for release of the free amine baseor of the ionized amine in the body are: inorganic acid salts such as,for example, the hydrogen chloride, sulfate and phosphate salts, andorganic acid salts, for example, as acetate, citrate, lactate orpyruvate salts.

The above mentioned salts can be prepared as outlined below, by mixingan adequate amount of THAM base to the acid in an appropriate molarratio. The THAM salt is next precipitated at an optimal pH in the propersolvent. THAM base can be added to the salt in order to obtain asolution of optimal pH for the condition to be treated. These salts canbe administered either intravenously or orally in the treatment ofvarious forms of acid-base balance disturbances.

For example: THAM hydrochloride is prepared by adding 100 m1. of 3 molarTHAM to 22 ml. of HCl. At pH 4.0 a precipitate is obtained and the saltis extracted with ethanol. This is a white crystal salt soluble in water(100%). THAM base is added to pH 7.0-8.0. This salt may be used in thetreatment of hypochloremic alkalosis. It may be administered orally as a500 mg. tablet, as a syrup or intravenously as a 0.3 molar sterilesolution at pH 7.40. THAM phosphate is prepared by mixing 100 ml. of 3 MTHAM with 22 ml. of 17 molar H PO At pH 4.50 a precipitate is formed.The salt is extracted with ethanol. This is a White crystal salt solublein Water (100% THAM base may be added to adjust pH to 7.0-8.0. Thiscompound could be used orally as a gastric antacid as a syrup or atablet alone or in combination with other salts.

THAM sulfate [(CH OH) CNH .H SO is prepared by adding 50 ml. of 6 M THAMto 9 ml. of 36 .7 N H 80 The solution is heated to 80 to dissolve theTHAM, and then cooled. The salt is then extracted with ethanol. T HAMbase may be added to pH 6.0. This salt could be used as a laxative in atablet tor a syrup.

Weak organic acids will also form salts with THAM, for instance THAMacetate 3,322,707 Patented May 30, 1967 One molar anhydrous acetic acidsolution (60 gm./l.) is added to one molar THAM solution (12 gm./l.) inequimolar amounts. This mixture is heated to C. for 3 minutes and cooledin an ice salt mixture. The precipitate appears at 5-10 C. This crystalis hydroscopic at room temperature. THAM base can be added to a solutionof this salt to pH 8.40. Therapeutic use as a gastric antacid and toalkalinize the urine. Administration by mouth of this solution flavoredwith a sugar syrup, 8-12 gm. daily to pnoduce an alkaline urine.

THAM lactate [CH OH) CNH .C H O is prepared in a similar way as a syrupand has the same indications.

citrate 4.0 gm. of citric acid anhydrous and 2.2 gm. of THAM aredissolved in 50%50% ethanol-ether'mixture. The mixture is cooled at 4 C.and a precipitate is formed. Separation is obtained by filtering througha Buchner funnel. The salt is a white crystal water soluble. THAM basecan be added to a solution of this salt till pH 8.50. Therapeutic use asa gastric antacid and for alkalinization of the urine. Administration bymouth as a 20% solution flavored with cherry syrup, 6-12 gm. a day.

The aforementioned salts of THAM are what might be termed conventionalsalts of THAM. In addition to these salts, however, there are THAM acidsalts and THAM complex salts which may be used in the treatment ofacidosis in accordance with my invention of US. Patent No. 3,055,805 butwhich, in addition, have added tributes, as will be evident from thediscussion which follows. The last mentioned salts are novelcompositions of matter and form the basis of the present invention.

The present invention relates to novel THAM salts formed by thecombination of THAM with an acidic therapeutic agent of limitedsolubility in water to form a THAM salt which is readily soluble inwater. The aforementioned term water includes body fluids. When thesalts of the present invention are administered in the body, the saltsbreakdown into THAM and the acidic active ingredient whereby the THAMcomponent serves in its own capacity as a antacid and the acidiccomponent efiects its own therapeutic activity. In addition, all thesesalts are sodium free, which is of great importance for all patients ona Na-free diet because of an underlying cardiovascular or kidneydisease. The preferred method of producing the novel THAM salts of thisinvention is to mix an adequate amount of THAM base to the acid in anappropriate molar ratio, the THAM salt is precipitated at optimal pH inthe proper solvent.

Examples of therapeutically active acidic components useful in formingnovel THAM salts in accordance with this invention are salicylic acid,acetylsalicylic acid, barbituric acid, S-ethyl-S (1methylbutyl)-2-thiobarbituric acid and ascorbic acid. The following areexamples of novel THAM salts, the optimal pH for administration of suchsalts and their therapeutic utility.

EXAMPLE 1.THAM SALICYLATE [(CH OH) CNH .C H O Mix 1.5 gm. salicylic acidand 1.2 gm. THAM dissolved in 2 m1. of ethyl alcohol. Heat for 3 minutesat boiling temperature of alcohol (70 0.). Cool to room temperature andadd 3 ml. of ether to precipitate salt. Separation by filtering throughBuchner funnel. White crystal, soluble in water.

Therapeutic use: In 220% lotion or ointment as an antiseptic in topicalapplication.

EXAMPLE 2.THAM ACETYLSALICYLATE [(CH OH) CNH .CH C0OC H COOH] (3.6 gm.of acetylsalicylic acid and 2.4 gm. of THAM dissolved in 5 ml. of H 0and heated for 35 minutes) 3 Mixture is cooled to C. and precipitateappears. Separation by filtering through Buchner funnel. White crystalsoluble in water.

Therapeutic use: Analgesic and antirheumatic agent. Administration bymouth as a tablet or in a syrup, 1-10 gm. daily. Intravenously as a 0.3molar solution.

EXAMPLE 3.THAM barbital a 3 2- 8 12 2 3] (2.6 gm. of barbituric acid and2.4 gm. of THAM dissolved in 10 ml. of H 0) Heat for 35 minutes toboiling point of solvent (100 C.). Cool down to 0 C. and the precipitateappears. Separate by filtering through Buchner filter. White crystalsoluble in water.

Therapeutic use: Sedative and hypnotic. Administration by mouth as atablet or a syrup (.030.1 gm.) daily. Intravenously as a sterile 0.3molar solution for anesthesia (0.5-1.5 gm.).

EXAMPLE 4 thiOpcntal [(CH2OH)3CNH2.C11H1702S] can also be made in asimilar way and has the same therapeutic applications as THAM barbital.

EXAMPLE 5.-THAM ASCORBATE 3CNH2-C5H8O6] (1.2 g. of THAM is added to 1.76gm. of ascorbic acid and dissolved in 5 ml. of H 0) The salt isprecipitated by addition of ethanol. This white crystal salt is solublein water.

Therapeutic use as a vitamin and as an anti-oxydant. Administration as atablet, 0.1 to 1 gm. orally, or in a sterile solution for intravenoustherapy.

Another feature of this invention is the provision of novel THAM metalcomplexes, for example, such as THAM aluminum, THAM copper and THAMZinc. These metal complexes are formed by combining a solution of THAMwith a solution of an appropriate metallic salt. In this case THAM actsas a chelate. The formation of a metal chelate of a weak base is usuallyaccompanied by the displacement of one or more acidic protons of thechelating agent by a metal ion, causing a drop in the pH of thesolution.

For example:

The reaction between a chelating agent and a metal salt will come to anequilibrium without completion of reaction because of the increase inacidity in solution during chelate formation. To overcome thisdifficulty, controlled pH must be used either by buffering the solu- 7tion or by gradually adding a base, preferably a weak is below the pH atwhich hydrolysis of the metal ion occurs (4.0-6.0). For example, a largeamount of aluminum chelate precipitates at pH about 5.0. The resultingsolution is warmed on a water-bath until the precipitate coagdllates.The solution is filtered and the precipitate washed with water andethanol. The chelate is dried in a vacuum dessicator to constant weight.

EXAMPLE 6.-THAM ALU MINUNI 2 a zl 2 This complex can be preparedaccording to the general method mentioned above. It can also be formedin the body when a composition of matter containing THAM and aluminumhydroxide is administered orally and comes into contact with thehydrochloric acid contained in the stomach. Such a composition of matterwould contain:

EXAMPLE 7 Mg. THAM sulfate [(CH OH) CNH .H SO 250 THAM base [(CH OH) CNH250 Aluminum hydroxide [Al(OH) 500 for a one gram tablet, 5 times a dayagainst gastric acidity. The same composition of matter could be made asa syrup using identical proportions of active ingredients.

Examples of additional metal Complexes that may be formed in accordancewith this invention is THAM zincate [[(CH OH) CNH Zn]. This compound isformed by combining THAM and zinc nitrate according to the generalmethod described above.

Therapeutic application: As an astringent and antiseptic for medical andveterinary use.

THAM copper [[(CH OH) CNH Cu] is another metal complex of THAM which isuseful for topical ap- .plication as an antiseptic for medical andveterinary usage.

A further aspect of this invention is the provision of a novel THAMsalt, namely THAM hydrofiuoride [(CH OH) CNH .HF], which may be preparedby the general method described hereinbefore, with respect to thereaction between THAM and an acid, and may be used as a dentifriceadditive, e.g., 0.20.4% solution of a pH 8.0.

This invention in its broader aspects is not limited to the specificsteps, methods and compositions described, but departures may be madetherefrom within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing its chiefadvantages.

What is claimed is:

1. A THAM salt or metal complex selected from the group consistnig ofTHAM barbital, THAM thiopental, THAM ascorbate and THAM aluminum.

2. A THAM salt according to claim 1 which is selected from the groupconsisting of THAM barbital.

3. A THAM salt according to claim 1 which is selected from the groupconsisting of THAM thiopental.

4. A THAM salt according to claim 1 which is selected from the groupconsisting of THAM ascorbate.

5. A THAM metal complex according to claim 1 which is selected from thegroup consisting of THAM aluminum.

No references cited.

ALEX MAZEL, Primary Examiner.

M. U. OBRIEN, Assistant Examiner.

1. A THAM SALT OR METAL COMPLEX SELECTED FROM THE GROUP CONSISTING OFTHAM BARBITAL, THAM THIOPENTAL, THAM ASCORBATE AND THAM ALUMINUM.
 2. ATHAM SALT ACCORDING TO CLAIM 1 IN WHICH IS SELECTED FROM THE GROUPCONSISTING OF THAM BARBITAL.